MULTIPLE-DOSE PHARMACOKINETICS OF TILUDRONATE IN HEALTHY-VOLUNTEERS

Objectives. A double-blind, placebo-controlled study was conducted to assess the pharmacokinetics and pharmacodynamics of the bisphosphonate tiludronic acid, administered once daily as sodium tiludronate 200, 4 00, 600 and 800 mg for 12 days. Four groups of ten subjects participat ed in the study, with a drug to placebo ratio of 4:1. Methods: Pre-dos e blood samples were taken on alternate days, starting on Day 1 and ad ditional samples were collected over 144 h following the final dose on Day 12. Urine was collected over 24 h after the final dose. Indices o f calcium homeostasis and biochemical markers of bone turnover were as sessed during the study as pharmacodynamic parameters. Tolerability wa s evaluated with special emphasis on renal function and gastrointestin al irritation. Adverse experiences were assessed at regular time inter vals. Results and conclusions: Steady state was attained from Day 4 (2 00 mg) or from Day 6 (400, 600 and 800 mg). Following the final dose o n Day 12, minimal plasma concentrations (C-min) ranged between 0.19 an d 1.5 mg . l(-1), and maximal plasma concentrations (C-max) between 1. 1 and 7.8 mg . l(-1) for the lowest and highest doses, respectively. A supra-proportional increase in C-max, AUC(24) and A(24)(e) With dose was observed, There was a linear relationship between the plasma tilud ronic acid and its urinary excretion rate, so, the disproportional ris e in C-max and AUC(24) With increasing dose could not be attributed to saturation of renal excretion. Certain indices of calcium homeostasis changed significantly during the study, but generally, became only pr ominent at the highest dose level of 800 mg. Total serum calcium and t he urinary calcium/creatinine clearance ratio fell, indicating depress ion of osteoclastic bone resorption, which was not revealed by serum o steocalcin levels probably because of the brevity of the treatment (12 days). In response to the decline in serum calcium, serum 1,25-dihydr oxyvitamin D-3 and intact PTH (1-84) levels increased. None of the saf ety parameters raised any concerns about the safety of sodium tiludron ate administered in this way.